Diphenyl-ureas,-thioureas,-guanidines and -parabanic acids

ABSTRACT

DIGUANYLHYDRAZONES OF DIPHENYL-UREAS,-THIOUREAS,-GUANIDINES AND -PARABANIC ACIDS THAT CONTAIN IN EACH OF THE TWO PHENYL RADICALS A META-OR PARA-POSITIONED ALKANECARBONYL GROUP, ESPECIALLY PARA,PARA&#39;&#39;-DIACETYL-DIPHENYLUREABIS-GUANYLHYDRAZONE OF THE FORMULA   BIS((4-(NH2-C(=NH)-NH-N=C(-CH3)-)PHENYL)-NH-)-CO   SALTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM DISPLAY A TUMOUR INHIBITING ACTIN AND ACT AGAINST PROTOZOAE AND AMOEBAE.

United States Patent e 3,560,551

Patented Feb. 2, 1971 3 560 557 processes for the preparation of the newcompounds or s preparations. The new compounds possess valuable ggg figgg gg a 'gg pharmacological properties, especially a tumour inhibitingAdrian Marx" Muttenz Switzerland assignor to action as is found in theanimal test, for example on the Ciba crporafion, New York, N 5 mouse.Furthermore, the new compounds act against pro- No Drawing.Continuation-impart of application Ser. No. tOZOae and amoebae,espeCiallY against yp for 594,386, Nov. 15, 1966, which is acontinuation-in-part example against Trypansoma gambiense and TlypanoofSer. No. 589,195, Oct. 25, 1966. This application soma congolense. Theymay therefore be used as chemo- J uly 11, 1967, Ser. No. 652,409therapeutics for treating tumours, as trypanocidal and Claims priority,application Switzerland, Nov. 19, 1965,

1O amoebicidal agents. Furthermore, they may be used as 15,988/ )33 66intermediates, for example in the manufacture of pharma- U S C] 26o 5011' c 9 Claims cologically active compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS ABSTRACT OF THE DISCLOSURE Thenew compounds may contain further substituents, for example on thenitrogen atoms of the guanidino nidines and -parabanic acids thatcontain in each of the group of the guanylhydrazone grouping, above alllower two Phfinyl radicals 3 meta- Para-Positioned fllkanecafaliphatichydrocarbon radicals, such as lower alkyl groups, bonyl group,especially para,para'-diacetyl-diphenylureafor example those mentionedabove, or in the aromatic bis-guanylhydrazone of the formula rings, forexample lower alkyl groups, such as those men- Diguanylhydrazones ofdiphenyl-ureas, -thioureas, -guasalts thereof and pharmaceuticalcompositions containing them display a tumour inhibiting action and actagainst protozoae and amoebae.

tioned above, or lower alkoxy groups, for example methoxy, ethoxy,propoxy or butoxy groups, or above all halogen atoms, such as chlorineor bromine atoms, or trifluoromethyl groups.

Particularly potent are the compounds of the formula X CROSS-REFERENCESTO OTHER APPLICATIONS and This is a continuation-in-part of myapplication Ser. R R No. 594, 386, filed Nov. 15, 1966 which is, inturn, a 5= continuatlon-m-part of my appllcatron Ser. No. 589,195, 40filed Oct. 25, 1966 (now abandoned). NH NH SUMMARY OF THE INVENTION 2The present invention relates to new guanylhydrazones, in which R hasthe above meaning and represents in the Especially it concernsdiguanylhydrazones of diphenylfirst place methyl and X represents animino group, a ureas, -thioureas, -guanidines and -parabanic acids that4 sulfur atom or more especially an oxygen atom, and the contain in eachof the two phenyl radicals a meta or compounds of the formula 0 H R O RA I H2N-C-NH-N= ll l C=NNH([|3NH2 1' iH NH O O para-positionedalkanecarbonyl group, above all correand sponding diphenyl-ureas,-thioureas, -guanidines and -parabanic acids that contain in each phenylradical a metaor para-positioned alkanecarbonylguanylhydrazone f 0 frouping of the formula H2NENHN=OQ H C=N |f 2 H NH o GN==C- (I) (I: inwhich G represents a guanidino group and R a lower H alkyl radical,preferably a methyl, ethyl, propyl, butyl or 0 pentyl radical, and theirsalts, as well as corresponding in which R has the above meaning andespecially para,

pharmaceutical compositions, their use in medicine, andpara-diacetyl-diphenylurea-bis-guanylhydrazone which,

for example, in the form of its dihydrochloride dihydrate produces inleucaemic (L 1210) mice on intraperitoneal administration in doses of 10to 30 mg. per kg. bodyweight a distinct life-prolonging elfect.

Furthermore para,para'-diacetyl-diphenylurea-bis-gua- 4 citric,ascorbic, maleic, hydroxymaleic or pyruvic acid; phenylacetic, benzoic,para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicylic orpara-aminosalicylic, embonic, methanesulfonic, ethanesulfonic,hydroxyethanesultonic, ethylenesulfonic acid; halogenbenzene-sulfonic,tolnylhydrazone and its therapeutically acceptable salts are 5uene-sulfonic, naphthalenesulfonic acids or sulfanilic acid; active in adose of about 30 to 50 mg./kg. i.p. in the methionine or tryptophan.

folloWlhg tumours of the mousei Letleaemla P P These or other salts ofthe new compounds may be used 153435, L 5178 Y, P 288, AK4, P 815, inascites, such for purifying the free bases by converting the free basesas Ehrlich carcinoma, and in spontaneous cancers of the into salts,separating the latter and then liberating the breast (2040 mg./kg.); andin the following tumours Of bases again. In view of the closerelationship between the the rat in doses of 50-75 mg./kg. i.p.: Walker256, T8 new compounds in the free form and in the form of their Guerinuterus-epithelioma, Flexner Joblin carcinoma. salts, what has been saidabove and herein after with On the basis of this evidence thepara,para-dia etylreference to the free compounds refers similarly alsoto p y -g nylhydrazone and its h p i y the corresponding salts whereverthis applies. acceptable salts can be administered in medicine in orderTh invention l concerns those difi ti f th to inhibit of Slow down theprogress or bring about process in which a compound obtainable asintermediate remission of the respective tumours especially in cases oft any stage f h process i d as tarting t i l d lymphatlemyelohlastoses,Such as para-leukoblast leukethe remaining process steps are carriedout, or in which a mia, myeloic leukemia, lymphatic leukemia, Hodgstarting material is formed in situ or used in the form disease,Reticulosarcoma, and in cases of other maligf a l Ilomfl of thelYIhPhomyelole y it y also he used The starting materials are known or,if they are new, in cases of epithelial tumours, such as of thegastro-intestican b repared by a method known per se.

Ilal tract, the respiratory Passages, the ul'ogehltal System For thereactions of the invention such starting materials (including tumours ofthe uterus, and Chorionic ePlthellare used as yield the above-mentionedpreferred comoma), tumours in the head and neck (larynx, tongue, poundsthroat), of the endocrine and other glands (cancer of The new compoundsmay be used f r example i h the breast, tumours of the Pallefeas, of thethyloltl gland form of pharmaceutical preparations which contain themfurthermore in as s 0f mesellehymal tumours shell or their salts inconjunction or admixture with an organic as tumours of bones, cartilagand muscles, as l In or inorganic, solid or liquid pharmaceuticalexcipient suitth C ntr l nervous y and also in eases of {hallgllant ablefor enteral, parenteral or local administration. Suitmix tllInOIlIS- Thedaily dose will y aeeortllhg the able excipients are substances that donot react with the nature of the illness and the condition of thepatient; new compounds, for example water gelatin, lactose, usually ltls g in most cases 2 P body starches, stearyl alcohol, magnesiumstearate, talcum, Weight Parenterally, lntfevenouslyvegetable oils,benzyl alcohols, gums, polyalkylene-glycols,

The P P '-diacetyl-dlphenylurea-blsguanylhydrawhite petroleum jelly,cholesterol or other known medizone and its therapeutically acceptablesalts do also synercinal excipiems The pharmaceutical preparations maybe, glstleally enhance the activity of Pther tumour'mhlbltmg forexample, tablets, dragees, capsules, suppositories, ointproducts, suchas arabin yly Therefore the e ments or creams, or in liquid formsolutions, suspensions tion comprises also pharmaceutical compositionscontain- 40 or emulsions They may be sterilized and/or may contain lhgPal'a,PaTa"dlaeetYl-dlphehylurea'bls'guanltlhiidrazene auxiliaries suchas preserving, stabilizing, wetting or emulor its therapeuticallyacceptable salts, in comb nation with if i agents, solution promoters,Salts for regulating the another tHm F-i Compound espeelally e e osmoticpressure or buffers. They may also contain other y y b and thethefapelltic use of Such eomposltlons r therapeutically valuablesubstances. The pharmaceutical of of p .p y ph y y preparations areformulated by known methods. They Z ne r a therapeutically acceptableSalt thereof Slmul' advantageously contain 10-50 mg. of the activesubstance taneously with arabinosyl-cytosin. per dosage unit.

The new compounds are obtained by known h f The new compounds may alsobe used in the form of Advantageously. a diphenyl-urea, -thi0urea,suamdme or feeding stuffs or additives to feeding stuffs, using, for-Pitrttbahlc acid that Contains in each of the two Phenyl 5O example,the conventional extenders and diluents or feedradicals a metaorpara-positioned alkanecarbonyl radii t ff respectively Such as a loweralkaheeafbonyl group, example The following examples illustrate theinvention. the acetyl, propionyl, butyryl or oenanthoyl group, isreacted With a guanylhydrazine. The guanylhydrazine is adr EXAMPLE 1vantageously used in the form of a salt thereof.

The reaction is carried out in the conventional manner. 39.2 grams ofaminoguanidine bicarbonate in ml. of

Depending on the reaction conditions and the starting Water are mixedwith 61.5 ml. of 6.17 N hydrochloric acid. materials used the endproducts are obtained in the free The resulting solution ofaminoguanidine hydrochloride is form or in the form of their salts or,if desired, the hymixed with 29.63 g. of para,para'-diacetyldiphenylurea drates, which are also included within the scope of the 60and then with 200 ml. of dimethylformamide and the mixinvention. Thesalts of the final products may be converted ture is heated withstirring for 10 hours in an oilbath at in a manner known per se, forexample with an alkali C. The batch is filtered, concentrated in vacuoto half or an ion exchanger, into the free bases. From the latter itsoriginal volume, and 150 ml. of water are added, the salts may beobtained by reaction with organic or incontents of the flaskcrystallizing. The batch is first crystalorganic acids, particularlythose which are suitable for 65 lized from ml. of dimethylformamide withthe addithe formation of therapeutically acceptable salts. Suitable tionof 200 ml. of water, then from 100 ml. of dimethylacids are, forexample: hydrohalic acid, sulfuric acids, formamide with the addition of200 ml. of ethanol. The phosphoric acids, nitric acid; aliphatic,alicyclic, aromatic resulting crystals melt at 238242 C. withdecomposior heterocyclic carboxylic or sulfonic acids, such as formic, htion and are para,para'-diacetyl-diphenylurea bis-guanylacetic,propionic, succinic, glycollic, lactic, malic, tartaric, 0 hydrazonedihydrochloride dihydrate of the formula 25 g. of the dihydrochlorideare poured into 1.5 liters settles out. It melts at 269 to 272 C. TheWater of crystalof boiling water and stirred to give a clear solution.The lization can be removed by drying above 100 C. in a solution isfiltered, cooled on an ice-water bath rapidly high vacuum. The anhydroussubstance is hygroscopic and to 30 C. and, before the dihydrochloridecrystallizes out rapidly reabsorbs 2 mols of water.m,m-Diacetyl-diphenylagain, 150 ml. of 2 N sodium hydroxide solution areadded 5 urea-bis-guanylhydrazone melting at 193 C., can be libin oneportion. The first amorphous precipitate soon beerated from thehydrochloride by means of concentrated comes crystalline on cooling. Thebatch is suction-filtered 1:1 ammonia solution. and the precipitatewashed on the filter with water and ethanol, to yieldp,p'-diacetyl-diphenylurea-bis-guanylhy- EXAMPLE 4 drazone melting at22l223 C. with decomposition. 7.81 g. of p,p'-diacetyl-diphenyl-thioureain 50 ml. of 20.42 g. (0.05 mol) of this compound are suspended indimethylformamide are added to a solution of 9.8 g. of 250 m1. ofabsolute ethanol, nd tre ted with 52 1, f aminoguanidine bicarbonate inml. of water and 15.4 2 N ethanolic methanesulfonic acid. 60 ml. ofwater are 0f hydrochloric acid 111 normal) and the batch addedsuccessively to the suspension with heating on a stirred in a stirringflask for 14 hours at 50 C. The clear water-bath until a clear solutionis formed. The solution 15 Solution is filtered and Cooled;crystallization takes Place is filtered, 300 ml. of absolute ethanol areadded and the g v- The reaction mixture is filtered w h suction productallowed to crystallize out. After filtering with and Washed With alittle Water and ethanol, to yield p,p'- suction and drying,p,p'-diacetyl-diphenylurea-bis-guanyldiacetyldiphenylthiourea-bis-guanylhydrazone-dihydrohydrazone-bis-methanesulfonatemelting at 1791 83 C. is chloride of the r ll a CH3 CH3H2NoNHN=h-NH-fi-NH-b=NNH-olvm2ncl ire S lie obtained. After drying in ahigh vacuum, the product in the form of crystals melting at 212214 C.The submelts at l90195 C. stance contains 1 to 2 mols of Water ofcrystallization, de-

EXAMPLE 2 pending on the degree of drying. 39.2 grams of aminoguanidinebicarbonate in 60 ml. of EXAMPLE 5 Water are mixed with 60 ml. of 6.43 Nhydrochloric acid. 61.5 ml. of hydrochloric acid 1:1 (6.17 normal) areThe resulting solution of aminoguanidine hydrochloride added to 39.2 g.of aminoguanidine bicarbonate, susis mixed with 29.63 g. ofpara,para'-diacetyl diphenylurea pended in 60 ml. of Water, to prepare aclear solution. and then with 200 ml. of dimethylformamide, and the mix-31.23 g. (0.1 mol) of m,.m'-diacetyl-diphenylthiourea, ture is heatedwith stirring for 5 hours in an oilbath at suspended in 200 ml. ofdimethylformamide, are added 150 C. The batch is then filtered,concentrated under to this solution and the Whole stirred for 14 hoursin a vacuum to half its original volume, and 300 ml. of absoba h a C. Threaction mi r is filtered. the clear lute ethanol are added, whereuponthe batch turns crystalsolution evaporated in vacuo, the residuedissolved in line; it is suspended in 200 ml. of water, suction-filtered250 ml. of water, filtered again from a turbidity and alandrecrystallized from 500 ml. of a 2:3-mixture of ethalowed tocrystallize. The crystals are isolated to yield nol and Water, Whileremoving part of the solvent under m,mdiacetyl-diphenylthiourea bisguanylhydrazone vacuum when all has dissolved and replacing it by freshdihydrochloride 0f the formula ([JH; CH3 H2N- -NHN=o C=NNHENH2.2HCI

NH S H NH'LNr absolute ethanol until crystallization sets in. Thecrystals melting at 200-205 C. with decomposition. obtained constitutepara,para'-diacetyl-diphenylurea-bisguanylhydrazone dihydrochloridedihydrate which is iden- EXAMPLE 6 tical with the product described inExample 1. 50 13-18 of -ip p y are EXAMPLE 3 added to a solution ofaminoguanidine hydrochloride, prepared from 17.55 g. of aminoguanidinebicarbonate in 19.6 grams (0.144 mol) of aminoguanidine bicarbonate 30ml. of water and 27.8 ml. of hydrochloric acid 1:1 are dissolved in amixture of 30 ml. of water and 29.3 ml. (6.15 N). After addition of ml.of dimethylformamide (0.18 mol) of 6.15 N hydrochloric acid. 14.85 gramsthe reaction mixture is stirred for 10 hours at 80 C. The (0.05 mol) ofmeta,meta'-diacetyl-diphenylurea in ml. clear solution is filtered andevaporated to half its volof di-methylformamide are added to thesolutionand the ume in vacuo, 1,3-bis-(para-acetylphenyl)-guanidine-bis- Wholeis rapidly heated to an internal temperature of guanylhydrazonetrihydrochloride of the formula (3H3 (IJHa H2NCHNN=CNH-fi-NHC=NNHCNH2.3HCl

I IH NH IUIH 100 C., then stirred on for 5 hours in an oilbathmaincrystallizing out. The crystals are separated by filtratained at C.,filtered and evaporated to dryness under tion and washed with water andethanol; M.P. 3l0 C. vacuum. The residue is dissolved in ml. of ethanoland 65 The 1,3 bis (para-acetyl-phenyl)-guanidine used as once moreevaporated to dryness. Finally, the residue is starting material may beprepared as follows: mixed with 50 ml. of ethanol and left to itself,whereupon 2.5 g. of sodium are dissolved in 100 ml. of absolutegradually very finely crystalline meta,meta'-diacetyl-diethanol. 31.24g. of p,p'-diacetyl-diphenylthiourea, susphenylurea bis guanylhydrazonedihydrochloride dipended in 200 ml. of ethanol, are added to thesolution.

hydrate of the formula 70 The resulting clear solution is heated for 1hour at 90 C.,

(3H3 CH3 H2N-("3NHN=C O b=N-NH-( JNH;.2H 01.21120 NH I NH then cooled to25 C., and 14.9 g. of methyliodide in 50 ml. of ethanol are addeddropwise. The batch is stirred for hours in a bath at 95 C. The clearsolution is filtered and ammonia gas is introduced into this solutiondirectly for 1 hour with ice-water cooling, 1 hour at room temperatureand 2 hours at 80 C. (internal temperature). The batch is cooled andfiltered 01f from the first crystallization which is discarded, thenevaporated to about 200 ml., and 1.4 liters of water are added. Thefirst oily residue soon solidifies. The supernatant water is poured oiland the residue allowed to stand with 300 ml. of ether. Crude 1,3 bis(para-acetylphenyl)-guanidine melting at 203-207" C. is obtained whichis used directly for the above described reaction.

In an analogous manner from l,3,-bis-(meta-acetylphenyl)-guanidine andaminoguanidine hydrochloride there can be obtained1,3-bis-(meta-acetylphenyl)-guanidine-bis-guanyl-hydrazonetrihydrochloride.

EXAMPLE 7 Tablets containing mg. ofp,p'-diacetyl-diphenylurea-bis-guanylhydrazone bis-hydrochloride may beprepared, for example with the following ingredients.

" tilled water so that in 1 ml. of solution 10.0 mg. of p,p-

diacetyldiphenylurea-bis-guanylhydrazonc bis methanesulfonate and 85.0mg. of mannitol are contained. The solution is filtered through amembrane filter No. 1 and filled into ampoules while being gassed withnitrogen. The fused ampoules are heated in an autoclave at 120 C. for 20minutes.

EXAMPLE 9 3.50 g. of N,N'-(para,para-diacetyl-diphenyl)-parabanic acidare suspended in 20 ml. of dimethylformamide. The suspension is pouredinto a solution of 3.92 g. of aminoguanidine bicarbonate in 6 ml. ofwater and 6.15 ml. of hydrochloric acid 1:] (6.15 N). The bath isstirred for 10 hours at a bath temperature of 80 C., then allowed tocool, and filtered. There are added 100 ml. of absolute ethanol, andafter some time the batch is filtered with suction. The mother liquor isevaporated under reduced pressure and the residue dissolved in 50 ml. ofethanol. Crystallization sets in again. The resulting thirdcrystallizate melts at 225231 C. and is the N,N-(para,para'-diacetyl-diphenyl)-parabanic acid bisguanylhydrazone-dihydrochloride-dihydrate of the formula Ingredients pertablet: Mg.

p,p-Diacetyl-diphenylurea bis guanylhydrazone-bishydrochloride 10.0Lactose 45.0 Wheat starch 20.0 Colloidal silicic acid 5.0 Arrowroot 14.5Talc 5.0 Magnesium stearate 0.5

Method p,p'-Diacetyl-diphenylurea bis guanylhydrazone bishydrochlorideis mixed with the lactose, part of the wheat starch and colloidalsilicic acid and then sieved. The remaining wheat starch is pasted withfive times the quantity of water on a steam-bath. With this paste thepowdery mixture, possibly with the addition of water, is kneaded until agranulatable mass is formed. This mass is pressed through a sieve havinga mesh of about 3 mm., dried at 45 C. and then pressed through a sievehaving a mesh of 0.8 mm. Arrowroot, talc and magnesium stearate areadded to hte dry granulate, the resulting mixture compressed intotablets having a gross weight of 100 mg.

EXAMPLE 8 An injection solution containing 10 mg. ofp,p'-diacetyl-diphenylurea bis guanylhydrazone bis-methanesulfonate maybe prepared, for example, as follows:

Ingredients:

p,p-Diacetyl-diphenylurea bis guanylhydrazonebis-methanesulfonate10.0mg. Mannitol-85 .0 mg. Distilled water to makel.0 ml.

Method The p,p-diacetyl-diphenylurea bis guanylhydrazonebis-methanesulfonate and mannitol are dissolved in dis- In a similarmanner, N,N'-(meta,meta'-diacetyl-diphenyD-parabanic acid bisguanylhydrazone-dihydrochloride can be obtained.

The N,N' (para,para-diacetyl-diphenyl) parabanic acid used as startingmaterial can be prepared as follows:

29.6 g. of para,para'-diacetyl-diphenylurea are suspended in 300 ml. ofchloroform, the suspension treated dropWise with 14.0 g. of oxalylchloride in 50 ml. of chloroform, and the whole stirred for 6 hours atan oil bath temperature of 70 C. The batch is filtered with suction andthe precipitate Washed with chloroform and then recrystallized from ml.of dimethylformamide. The crystallizate is considerably contaminatedwith starting material. 011 addition of 100 ml. of ethanol to the motherliquor, N,N (para,para-diacetyl-diphenyl) parabanic acid of meltingpoint 259262 C. is obtained.

What is claimed is:

1. A member selected from the group consisting of compounds of theformula in which G stands for guanidino, R for lower alkyl, Ph for amember selected from the group consisting of metaphenylene, andpara-phenylene, and Z for a group of the formula and their acid additionsalts of therapeutically acceptable acids.

2. A product as claimed in claim 1 in the form of an acid addition saltthereof with a therapeutically acceptable acid.

3. A product as claimed in claim 1, in which G stands for guanidino, Rfor lower alkyl, Ph for para-phenylene and Z for the group of theformula 10 or an acid addition salt thereof with a therapeuticallyacceptable acid.

6. A product as claimed in claim 5 in the form of an acid addition saltthereof with a therapeutically acceptable acid.

7. A product as claimed in claim 1, which product is theIn,'m'-diacetyl-diphenylurea-bis-guanylhydrazone or an acid additionsalt thereof with a therapeutically acceptable acid.

8. p,p'-Diacetyl-diphenylurea bis guanylhydrazonebis-mthanesulfonate.

9. p,p'-Diacetyl-diphenylurea bis guanylhydrazonedihydrochloride.

References Cited UNITED STATES PATENTS 12/1957 Meiser 26050l.l4

cal News, p. 31.

BERNARD HELFIN, Primary Examiner M. W. GLYNN, Assistant Examiner US. Cl.X.R.

